The identity, rate of synthesis, and metabolic modification of non-histone chromosomal proteins will be studied in neonatal and regenerating liver and liver neoplasms of the rat in order to characterize those aspects associated with malignant growth. The Morris series of transplantable hepatomas will be used in these studies because they provide the opportunity to correlate changes in nuclear proteins with growth rate. To further delineate the relationship between growth rate and metabolism of non-histone chromosomal protein, the influence of drugs which inhibit DNA or protein synthesis will be examined. The incorporation of isotope-labeled phosphate and amino acids will be measured in nuclear proteins separated initially according to solubility in sodium chloride solutions of increasing concentration. Subsequent separation will be made by polyacrylamide gel electrophoresis and isoelectric focusing. Such studies could reveal the degree of coupling between DNA replication and the metabolism of nuclear proteins. Isolation of those nuclear proteins which appear most characteristic of normal liver or hepatomas will be performed by preparative isoelectric focusing. The potential of these proteins to regulate DNA synthesis and gene expression will be tested in preparations of normal and neoplastic liver. This examination will be at the level of the whole cell with cultured Novikoff hepatoma cells and at the organelle level with isolated nuclei or chromatin. Particular attention will be directed to the action of nuclear proteins whose concentration is diminished in tumors to see if these proteins can exert a regulatory influence on DNA replication and transcription and, perhaps, inhibit tumor growth.